2. Academic Validation
  3. Cotargeting DNA topoisomerase II enhances efficacy of RAS-targeted therapy in KRAS-mutant cancer models

Cotargeting DNA topoisomerase II enhances efficacy of RAS-targeted therapy in KRAS-mutant cancer models

  • J Clin Invest. 2026 Feb 16;136(4):e197192. doi: 10.1172/JCI197192.
Rongzhong Xu 1 2,  Dongsheng Wang 2,  Guangzhi Ma 2 3,  Xun Yuan 4,  Qian Chu 4,  Songqing Fan 5,  Rener Zhang 6,  Pan Du 6,  Shidong Jia 6,  Ticiana A Leal 2 7,  Suresh S Ramalingam 2 7,  Zhen Chen 2 7,  Shi-Yong Sun 2 7
Affiliations

Affiliations

  • 1 Clinical Medical Center of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 2 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 3 Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China.
  • 4 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 6 Predicine, Inc., Hayward, California, USA.
  • 7 Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
PMID: 41697749 DOI: 10.1172/JCI197192
Abstract

The approval of sotorasib and adagrasib as the first KRAS G12C inhibitors has made the Ras oncogene a druggable target. However, they have modest objective response rates and short response durations. Therefore, strategies for improving RAS-targeted Cancer therapy are urgently needed. Here, we found that both sotorasib and adagrasib promoted Topoisomerase IIα (Topo IIα) proteasomal degradation in KRAS G12C-mutant Cancer cells and induced DNA damage and Apoptosis. In cell lines with acquired resistance to sotorasib, elevated Topo IIα levels were detected. TOP2A overexpression in sensitive KRAS G12C-mutant cells conferred resistance to sotorasib, whereas TOP2A knockdown in sotorasib-resistant cell lines sensitized the cells to sotorasib. Moreover, the combination of a KRAS G12C inhibitor such as sotorasib with a Topo II Inhibitor such as VP-16 synergistically decreased the survival of sotorasib-resistant Ras G12C-mutant cells with augmented induction of DNA damage and Apoptosis, effectively inhibited the growth of sotorasib-resistant tumors, and delayed or prevented the emergence of acquired resistance to sotorasib in vivo. Collectively, our results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of RAS-targeted Cancer therapy, providing a strong scientific rationale for targeting Topo II to improve RAS-targeted Cancer therapies.

Keywords

Apoptosis; Cell biology; Drug therapy; Lung cancer; Oncology.

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